Therapeutic sulfonamide compositions



Patented Oct. 1 l, 1949 OFFICE THERAPEUTIC SULFONAMIDE COMPOSITIONSDavid Lehr, New York, N. Y.

No Drawings Application August 18, 1945, erial No. 811,445

3 Claims. (Cl. 167-515) 1 This invention relates to novel compositionshaving new and valuable therapeutic properties. A principal object ofthe invention is to provide sulfonamlde drugs of lower toxicity, morecommay be maintained in the body because of certain toxic reactionswhich increase in frequency and severity with increasing sulfonamideblood concentrations in the body, although there may be considerablevariations with regard to the particular sulionamide employed and alsowith regard to the individual patient treated. These untoward reactionsconstitute a significant drawback in the therapeutic employment ofsulfonamides.

One of the most frequent and most serious of the toxic reactionsencountered in the administration of sulfonamide drugs is renalobstruction. This has been shown to be due to the dep sition ofsulfonamide crystals and the formation of solid sulfonamide concrementsin the urinary tract, which adversely ailects the kidney functions bothby mechanical obstruction and by damaging the kidney parenchyma.

I have found that renal toxicity due to the formation of renalconcrements can be greatly reduced or eliminated without decreasing thetherapeutically desirable concentrations of the drugs, or even with anactual increase in drug concentrations, and that all desirabletherapeutic effects may be obtained to the same degree or even to ahincreased degree by means of mixtures of two or more sulfonamide drugsof difierent molecular constitution.

I have found that various sulfanilamide derivatives when mixed in thesame solvent (water, urine) do not influence each other with regard totheir individual solublllties. In other words, the

solubility of each component is about the same as if it were the onlycompound present in the solvent. The sulfonamide concentration of asaturated sulfonamide mixture corresponds therefore, to the sum of thesolubilitles of all its components. This is true whether the drugs areclosely related in structure or are of substantially differentstructural composition. This substantially additive solubility is foundto exist with mixtures of homologous sulfonamide drugs, such assulfadiazine (2-sulfanilamidopyrimidine) and sulfamerazine(2-sulfanilamido-4-methylpyrimidine), with mixtures of isomericsulfonamide drugs, such as sulfadiazine and sulfapyrazine (2-sulfanilamidopyrazine) and with mixtures of sulfonamide drugs ofrelatively unrelated chemical structure, such as, sulfadiazine andsulfathiazole (Z-sulfanilamidothiazole). I

By means of the mixtures of sulfonamide drugs of the invention, it ispossible to maintain highly effective concentrations of the drugs in thebody fluids while preventing the concentration of any single drug in themixture from closely approaching levels at which, in accordance withgeneral clinical experience, renal toxic effects are known to appear.The sulfonamide drugs in the mixture may be selected and proportioned asto produce the best therapeutic eflect or combination of effects inaccordance with the particular localization of the infection (lungs,meninges, urinary tract, etc.) and also in accordance with the type ofthe invading organism. If desired, either to obtain a specialtherapeutic effect, or to still further reduce the concentration of oneor more of the drugs in the composition, mixtures of three or moresulfonamide drugs may be provided, for example, sulfathiazole,sulfadiazine, sulfamerazinc and sulfamethazine (2-sulfanilamido-4,6-dimethylpyrimidine) The component sulfonamide drugs of the compositionsoi. the invention may include N -heterocyclic compounds suchlas thosespecifically mentioned above, non-cyclic N -substitution products suchas sulfaguanidine, and N -substitution products such assuccinylsulfathiazole, and, in general, compounds of the general formulapo e to express this range of proportions.

- The remarkable reduction in toxicity provided by the compositionsofthe invention is strikingly illustrated by the following seriesof acuteand chronic toxicity tests on albino rats using the sodium salts ofsulfadiazine (NaSD) and sulfathiazole (NaST) and mixtures of the two:

ACUTE TOXICITY Drug), gm. per Kg.

Ody weight No. Per of C t Remarks Single intra- Suliona- Alli- 11peritoneal mide mals injection total oiamount NaSD,1. 6. 1.5 10 9o Diedwithin 1 to a days. Na% LL... 1. 1 16 67 Died within 1 to 4 days. Na 1 a.10 Mixture or one half of NEST each of the above dosages. Completerecovery.

CHRONIC TOXICITY Drug, per K body weight N o. of Per Anicent RemarksDaily intra- Sulionamals Death peritoneal inmide total jection oiamountN aSD, 0.9 0. 9 100 Died within 3 to 6 days. NaST, 0.9.. 0. 9 10 100Died within 1 to4 days. ggg gfg- 0.9 10 40 Died within 3 to 1 days.

The animals were injected for a maximum of 6 consecutive days.

of renal obstruction, following administration of the mixedsulfonamides, as the chief reason for the strikingly low toxicity of themixture. This could be inferred in particular from a comparison ofthenon-protein nitrogen levels in the blood and from comparative follow-upstudies of the sulfonamide concentration in blood and urine atpredetermined intervals. When a dosage representing the same totalsulfonamide content was used, the sulfonamide blood levels obtained withthe mixture were much higher than from sulfathiazole alone, and onlyslightly lower than from sulfadiazine alone. The average totalsulfonamide values (mean of 10 animals) for the dosages used in theacute toxicity study were, after 24 hours, for sulfadiazine: 121 mg. percent, for sulfathiazole: 45 mg. per cent, and forsulfadiazine-sulfathiazole: 85 mg. per cent. After the same interval,the urinary drug excretion per rat (means of 10 animals) had reached 29mg.

for sulfadiazine, 34 mg. for sulfathiazole, and 72 mg. forsulfadiazine-sulfathiazole. The strikingly high renal excretion of themixture from blood levels distinctly lower than in the sulfadiazinegroup, indicated a diminution or even absence of renal obstruction inthe animals receiving the sulfonamide combination. Further support forthis viewpoint was derived from the marked difference in the non-proteinnitrogen values of the surviving rats 48 hours after the drug injection(mean values: sulfadiazine group 182 mg. per cent, sulfathiazole group120 mg. per cent, sulfadiazine-sulfathiazole group 82 mg. per cent) andalso from post mortem examinations, especially "of the urinary tract,which showed little or no renal damage in the animals treated with themixture as compared to very definite renal damage when either of thesulfonamides was given separately in the same total dosage.

The experimental observations on laboratory animals were substantiatedby clinical trials with the sulfadiazine-sulfathiazolecombination whichdemonstrated a striking reduction in the incidence of crystalluria andcomplete absence of renal toxic eifects despite the intentional omissionof adjuvant alkali therapy.

. Some of the sulfonamide compositions of the invention show, inaddition to the decreased renal toxicity, a definite improvement in thetherapeutic effect. In other words, sulfonamide mixtures may show abetter curative eifect than any one of the component drugs. Thisviewpoint was derived from clinical observations. It was confirmed by invitro antibacterial studies which disclosed that, for example, mixturesof equal parts of sulfathiazole and sulfadiazine or of sulfadiazine andsulfamerazine, were, in many instances, significantly more eifectiveagainst strep. hemolyticus, staph. aureus, pneumococcus and E. coli thanany of the three drugs used alone in the same total concentration.

The compositions of the invention may be dispensed in powder form,compressed into tablets, in solution (particularly in the form of thesodium salts) or in any other desirable form, and any desirable andcompatible substances may be added thereto to aid or improve thecompounding, dispensing or. administration of the compositions. Thecompositions defined in the claims hereof are intended to include thesalts of the defined components.

I claim:

1. A therapeutic composition prepared for the internal administration ofsulfonamide drugs consisting of a mixture of substantially equal amountsof at least two p-aminobenzenesulfonamide compounds differentlysubstituted at the N nitrogen by a radical selected from the groupconsisting of heteroatomic chains and heteroatomic rings, the amount ofeach component in each dose being substantially less than the fulldosage of such component of the mixture that would be given if suchcomponent were given alone, whereby the renal toxicity is substantiallyreduced without reduction of the therapeutic effeet as compared with thetoxicity and therapeutic efiect of each of said mixture components whengiven singly in full dosage.

2. A therapeutic composition prepared for the internal administration ofsulfonamide drugs consisting of a mixture of substantially equal amountsof 2-sulfanilamidothiazole and 2-sulfanilamidopyrimidine, the amount ofeach component in each dose being substantially less than the fulldosage of such component of the mixture that would be given if suchcomponent were given alone, whereby the renal toxicity is substantiallyreduced without reduction of the therapeutic eilect as compared with thetoxicity and therapeutic efiect of each of said mixture components whengiven singly in full dosage.

3. A therapeutic composition prepared for the internal administration ofsulfonamide drugs consisting of a mixture of substantially equal amountsof 2-sulfanilamidothiazole and 2-sulfani1amido-4-methylpyrimidine, theamount of each component in each dose being substantially less than thefull dosage'of such component of the mixture that would be given if suchcomponent were given alone, whereby the renal toxicity is substantiallyreduced without reduction of the therapeutic efiect as compared with thetoxicity and therapeutic effect of each of said mixture components whengiven singly in full dosage.

DAVID LEHR.

REFERENCES CITED UNITED STATES PATENTS Name Date Stribllng Dec. 4, 1944Number OTHER REFERENCES

